Peroxide-containing compounds, such as artemisinin, have demonstrated potent antimalarial activity, but the synthesis of these targets is generally laborious and expensive. This can be attributed to a lack of synthetic methods available for the installation of the notoriously labile oxygen-oxygen bond. Ultimately, this proposal will make new methods available for peroxide incorporation that can be directly applied to the synthesis of biologically active natural products. The objective of this application will be to develop methods for the regio- and stereoselective installation of sensitive peroxide functional groups and their transformation to other useful peroxide-containing scaffolds. The central hypothesis is that unsaturated or strained systems can be activated with the appropriate reagents, such that intra- or intermolecular attack by peroxide nucleophiles will provide cyclic and acyclic peroxide structures. To test the hypothesis, the research will focus on the following specific aims: 1. Develop electrophilic cyclizations of bis(hydroperoxy)acetals onto activated alkenes to prepare endoperoxides. The goal will be to develop highly regio- and diastereoselective cyclizations onto olefins with bis(hydroperoxy)acetals. 2. Develop nucleophilic opening of ([unreadable]-lactones for the preparation of cyclic, functionalized peroxides. This proposal will focus on the activation of p-lactones for cleavage of the alkyl C-O bond with pendant peroxide nucleophiles 3. Develop alkyne activation and rearrangement for the synthesis of [unreadable]-peroxyketones. The intramolecular cyclization of aldehydes and ketones onto activated alkynes will be optimized in the presence of peroxide nucleophiles. Treatment of the peroxyenol acetal products with a Lewis acid will initiate a Petasis-Ferrier rearrangement providing ([unreadable]-peroxy ketones which can be isolated in the absence of a base. The development of these methods will have an overall positive impact by expanding the utility for peroxide synthesis and manipulation, providing rapid access to the structurally important features of these bioactive molecules. The proposed research is significant because it will make compounds readily available for testing to identify new medicinal targets, not only for malaria, but for cancer as well as other diseases. PUBLIC HEALTH RELEVANCE: The methods described in this proposal will allow for the rapid, efficient synthesis of peroxide-containing compounds, many of which have been identified as potent antimalarial agents. New peroxide structures will also be accessed using the proposed methods. The proposed research will have a significant impact on the treatment of malaria, a serious world health problem, as well as other deadly diseases.